Mono ester of dicarboxylic acid

ABSTRACT

Optically active mono-esters of dicarboxylic acid of the formula III: ##STR1## being useful as intermediates for preparing optically active natural products or medicines; asymmetric synthesis process for preparing thereof being characterized by the reaction of an acid anhydride with an (R)- or (S)-arylacetic acid derivative; and the key substances therefor are also claimed.

This application is a divisional application of patent application Ser.No. 07/448,867, filed Dec. 12, 1989, now U.S. Pat. No. 5,047,574.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is useful in the asymmetric syntheses of thevarious compounds originated from natural products. In more detail, thepresent invention relates to the mono esters of dicarboxylic acids whichare useful in preparing optically active prostaglandins or the like andprocess for the production thereof.

2. Prior Art

The Diels-Alder reaction (EP-A-0312906), enzymatic hydroylsis of diestermoiety or the like is well known as methods for production of opticallyactive half-esters. However, even by such methods, it has been sodifficult to prepare a stereochemically pure compound economically on alarge scale due to stereochemical impurities, or complicated reactions.

It is significantly useful for the production of various medicinalcompounds as well as organic ones from natural sources, if keyintermediates are obtained in a high optical purity.

The present invention is designed for syntheses of compounds in muchhigher optical purity. It is achieved by a stereoselective reaction andby a very easy removal of a small amount of by-products produced in thereaction.

Moreover, the present invention has also an intention of achieving theabove-mentioned reaction easily with the inexpensive reagents.

SUMMARY

This invention provides the optically active mono esters of dicarboxylicacid of the formula III: ##STR2## and further provides a process forpreparing the compound of the formula III characterized by the reactionof the σ-symmetric dicarboxylic anhydride with arylacetic acidderivative and the removal of arylacetic acid residue. The compounds ofthe formula III are useful as intermediates for preparing opticallyactive natural products and medicines.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As a result of the extensive study, the inventors have found that themono esters of dicarboxylic acids having the desired configuration canbe prepared by reacting σ-symmetric acid anhydrides with (R)- or(S)-arylacetic acid derivatives. The present invention is based on thisfinding.

Though the details are described hereinafter, the by-product whichresults from this reaction can be removed easily by singlecrystallization. The asymmetric synthesis the present invention providesis applicable to various σ-symmetric acid anhydrides. The consequentmono esters of dicarboxylic acids are very important as theintermediates for production of such useful compounds obtained fromnatural sources as prostaglandins, terpenes, aminosugers, nucleotides,alkaloids, and so forth.

The present invention provides these important intermediates, i.e., anoptically active mono-ester of a dicarboxylic acid of the formula III:##STR3## wherein R¹ is optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted aryl, or optionallysubstituted aralkyl, --X-- is --O--, --S--, --O--O--, --(CH₂)m--,##STR4## wherein m is an integer of 0 to 4, R² is hydrogen, methyl, orethyl, and R³ is hydrogen, methyl, benzyloxycarbonyl, or formyl;##STR5## wherein n is an integer of 0 to 3, R² is the same as definedabove, and R⁴ is hydrogen, methyl, or ethyl; and Z is hydrogen, loweralkyl, or phenyl, excepting those which m and n are identically zero or(1S,2R,3S,4R)-7-oxabicyclo[2.2.1]heptan-2,3-dicarboxylic acid 2-methylester.

And also the present invention provides the asymmetric synthesis processfor prepareing mono esters of dicarboxylic acid of the formula III:##STR6## wherein R¹, X, Y, and Z each is the same as defined above;being characterized by the reaction of an acid anhydride of the formulaI: ##STR7## wherein X, Y, and Z each is the same as defined above; withan (R)- or (S)-arylacetic acid derivative of the formula: ##STR8##wherein M¹ is hydrogen or metal atom, R⁵ is hydrogen, optionallysubstituted alkyl, optionally substituted aralkyl, and Ar is optionallysubstituted aryl; to give an ester of arylacetic acid derivative of theformula II: ##STR9## wherein R⁵, X, Y, Z, and Ar each is the same asdefined above; and subsequent esterification of the said ester II tointroduce R¹ followed by removal of the arylacetic acid residue orsubsequent reaction of the said ester II with a compound IV of theformula:

    R.sup.1 OM.sup.2                                           IV

wherein R¹ is optionally substituted alkyl, optionally substitutedalkenyl, menthyl, optionally substituted aryl, or optionally substitutedaralkyl and M² is alkali metal or alkaline earth metal.

Moreover, the present invention provides the highly pure key substances,which are produced throughout the reaction process, i.e., the monoesters of (R)- or (S)-arylacetic acid derivative of the formula:##STR10## wherein R⁵, X, Y, Z, and Ar each is the same as defind above.

The present invention is explained in more detail by referring to thefollowing reaction schemes.

Preparation of mono esters of trans-dicarboxylic acids Method A

Method Using (R)-Arylacetic Acid Drivatives ##STR11## wherein R¹, R⁵, X,Y, Z, Ar, and M¹ each is the same as defined before.

Step 1

A prochiral cyclic anhydride having σ symmetry shown by the compound Iis allowed to react with a (R)-arylacetic acid derivative in a solventto give an aimed product II-D.

The reaction is achieved at a temperature of about -100° C. to about 50°C., preferably, at about -78° C. to about 0° C. within about several tenminutes to several hours.

As a solvent, tetrahydrofuran, diethyl ether, diisopropyl ether,dioxane, 1,2-dimethoxyethane, n-hexane, DMSO, toluene, HMPA, and thelike are exemplified.

Depending on the arylacetic acid derivative subjected to the reaction,two types of the aimed products II-D can be obtained. A free carboxylicacid type is represented by II-D(a) and an ester type is represented byII-D(e). Being crystallized easily, the compound II-D(a) can beseparated from impurities and subjected to next reaction. The compoundII-D(e) is subjected, if necessary, to deprotection in order to convertinto the compound II-D(a), which can be subjected to the next reaction.

The deprotection is preferably conducted under neutral to acidicconditions. The ester bond between the arylacetic acid residue andring-attached carbonyl must be retained during the deprotection.Therefore, alkali conditions are not suitable for this deprotection,since the said ester bond may be cleaved under such conditions. Usually,the deprotection is carried out by catalytic hydrogenoysis usingpalladium carbon under neutral conditions. In case that the compoundII-D has any other functional groups liable to be reduced or doublebonds in X or Y, it is hydrogenated at those sites and sometimes givessingle bonds consequently. If deprotections without any influence tothose sites would be desired, it is recommended that the reaction iscarried out under acidic conditions using such reagent astrifluoroacetic acid, aluminum chloride, zinc-acetic acid or the like.The desired protecting group may be removed by thermal decompositionwith LiI, LiCl, NaCl, or the like.

Step 2

The aimed compound III-D is prepared by the transesterification with thecompound of the formula IV:

    R.sup.1 OM.sup.2                                           IV

wherein R¹ and M² each is the same as defined above, followed by thestereoselective isomerization.

The compound of the formula IV includes an alkoxide, aryloxide,alkenyloxide, menthyloxide, aralkyloxide, or the like with an alkalimetal or alkaline earth metal.

The alkali metal or alkaline earth metal alkoxide includes sodiummethoxide, lithium methoxide, magnesium ethoxide, or the like.

The alkali metal or alkaline earth metal aryloxide includes sodiumphenoxide, lithium phenoxide, magnesium phenoxide, sodium α-naphthoxide,lithium β-naphthoxide, or the like.

The alkali metal or alkaline earth metal alkenyloxide includes sodiumallyloxide, lithium allyloxide, magnesium allyloxide, or the like.

The alkali metal menthyloxide includes sodium menthyloxide, lithiummenthyloxide, or the like.

The alkali metal aralkyloxide includes sodium benzyloxide, lithiumbenzyloxide, or the like.

As a solvent, methanol, ethanol, allylalcohol, phenol, or the like isused, if necessary, menthyl alcohol, pyridine, tetrahydrofuran, or thelike may be added.

The reaction is achieved at a temperature of about -30° C. to about 150°C., preferably, at about 0° C. to about 80° C. within about 3 to about10 hours.

In the Step 1, a small amount of compound represented by the followinggeneral formula II'-D: ##STR12## wherein R⁵, X, Y, Z, and Ar each is thesame as defined above; is obtained as a by-product. If necessary, inorder to remove the said by-product quantitatively, it may be convertedinto a dicarboxylic acid II'-D(a), which remains in mother liquor afterrecrystallization, by removing the protection group. And the pure aimedproduct II-D can be applied to the next step 2. The product II-D(e) inthe step 1 may be subjected to next reaction without isolation. Theester may be purified by the chromatography.

Method B

Method Using (S)-Arylacetic Acid Derivatives ##STR13## wherein R¹, R⁵,X, Y, Z, Ar, and M¹ each is the same as defined before.

Step 1

According to Step 1 previously mentioned for the (R)-arylacetic acidderivatives, the compound I is allowed to react with an (S)-arylaceticacid drivative to give an aimed compound II-L. Depending on thearylacetic acid derivatives subjected to the reaction, two types of theaimed products II-L can be obtained. The free carboxylic acid type andthe ester type are represented as II-L(a) and II-L(e), respectively. Thecompound II-L(a) can be isolated easily by crystallization.

Step 2

According to the fore-mentioned Step 2 for the D isomer, the compoundII-L prepared in Step 1 is allowed to react with bases to give an aimedcompound III-L.

In the above Step 1, a small amount of the compound II'-L represented bythe following general formula II'-L: ##STR14## wherein R⁵, X, Y, Z andAr each is the same as defined before is obtained as a by-product. Thesaid by-product can be removed by the same manner as in the case thatarylacetic acid derivatives of D-isomer are used. The mixture whichcontains the compound II'-L(e) can be also applied to the next reactionwithout isolation. The ester can be also purified by the chromatographyas mentioned above.

If necessary, compound II'-D or II'-L can be transformed into thedesired III-L or III-D, respectively by the reaction of Step 2.

Preparation of mono esters of cis-dicarboxylic acids Preparation ofCompound III-D-2

The compounds II (II-D, II'-D, II-L, and II'-L) prepared by the samemanner as in Step 1 of Methods A or B for mono esters oftrans-dicarboxylic acids are used. ##STR15## In the above reactionscheme, R⁵ ' is optionally substituted alkyl, optionally substitutedalkenyl, menthyl, optionally substituted aryl, or optionally substitutedaralkyl and R¹, X, Y, and Z each has the same meaning as defined above.

Step 1

In this step, R¹ moiety is introduced by the esterification of the freecarboxyl of the compounds II-D or II'-L.

The esterification is carried out retaining the ester linkage betweenarylacetic acid residue and ring-attached carbonyl and the configurationat 2-position. The reaction is carried out in an usual manner usingdiazo-compound (e.g., diazomethane, diazoethane, diphenyldiazomethane,phenyldiazomethane), alcohol (e.g., methanol, ethanol, propanol,isopropanol, tert-butanol, benzyl alcohol, menthol, phenol, substitutedphenol (nitrophenol, methylphenol, chlorophenol, methoxyphenol),naphtol, or the like which have a desired R¹ formative group. In orderto facilitate the reaction, an acid such as p-toluenesulfonic acid,formic acid, sulfuric acid, hydrochloric acid, or the like may be added.

Step 2

In this step, the cis type compound of the present invention III-D-2 isprepared by the cleavage of the ester linkage between arylacetic acidresidue and ring-attached carbonyl.

As the configuration must be retained during the reaction, the reactionis usually carried out reductively using palladium-carbon under neutralconditions.

Preparation of Compound II-L-2 ##STR16##

In the above reaction scheme, R¹, R⁵ ', X, Y, and Z each has the samemeaning as defined above.

The compound III-L-2 is prepared from the compound II-L or II'-D in thesame manner as in the above Steps 1 and 2 for III-D-2.

The arylacetic acid esters, the compounds of the present invention ofthe formula II, have four types of stereoisomers II-D, II'-D, II-L, andII'-L.

The mono esters of dicarboxylic acid, the compounds of the presentinvention of the formula III, have four asymmetric carbon atoms,therefore, they have eight types of stereoisomers. This inventionincludes all of them, that is, the compounds having the configurationshown by the following formulas; ##STR17## wherein, R¹ X, Y, and Z eachhas the same meaning as defined above, and their enantiomers.

The following explanations are given for the terms used in the abovedefinition.

The term "alkyl" includes methyl, ethyl, isopropyl, n-propyl, n-butyl,isobutyl, t-butyl, sec-butyl, pentyl, neopentyl, and the like.

The term "alkenyl" includes 2-propenyl, 2-butenyl, 3-butenyl,2-methyl-2-propenyl, 3-methyl-3-butenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, prenyl, and the like.

The term "aryl" includes phenyl, α- or β-naphthyl, and the like.

The term "aralkyl" includes benzyl, phenethyl, naphthylmethyl, and thelike.

The term "metal atom" chiefly refers to alkali metal atom which includeslithium, sodium, potassium, and the like and alkalin earth metal atomwhich includes magensium, calcium, and the like and also refers to zincand the like.

The term "bicycle" includes norborane type (e.g., bicyclo[2.2.1]heptane,bicyclo[2.2.1]hept-5en, or the like), 7-oxabicyclo[2.2.1]heptane,7-oxabicyclo[2.2.1]hept-5-ene, 7-azabicyclo[2.2.1]heptane,7-azabicyclo[2.2.1]hept-5-ene, 7-thiabicyclo[2.2.1]heptane,7-thiabicyclo[2.2.1]hept-5-ene, and the like.

As the acid anhydride, a bi- or tricyclic anhydride having σ-symmetrycan be applied.

The substituent, which may exist on previous mentioned alkyl, alkenyl,aryl, and aralkyl includes above-mentioned alkyl and alkoxy, halogen,amino, amino derivative, nitro, and the like.

The term "alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy,pentyloxy, and the like.

The term "halogen" includes fluorine, chlorine, bromine, and iodine.

The term "amino derivative" includes hydroxyamino, alkylamino, and thelike.

The following examples and referential examples are included to explainthe embodiment of the present invention in more detail, but these arenot intended to limit the scope of the invention.

The abbreviations used throughout the tables, examples referentialexamples have the meaning as shown below.

Me: methyl,

CH₂ Ph: benzyl,

Et: ethyl,

CHPh₂ : benzhydryl,

Bu: butyl,

Ph: phenyl,

THF: tetrahydrofuran,

DMF: dimethylformamide,

HMPA: hexamethylphosphoramide,

D-Mande: D-mandelic acid and its ester,

L-Mande: L-mandelic acid and its ester,

PCC: pyridinium chlorochromate, and

PMB: p-methoxybenzyl.

EXAMPLE 1 Preparation of(1S,2R,3S,4R)-bicyclo[2.2.1]hept-5-en-2,3-dicarboxylic acid, 2-(benzylD-mandelate) ester II-1-D(e1) ##STR18##

In a nitrogen atmosphere, a solution of benzyl D-mandelate (5.33 g, 22.0mmol) in 50 ml of THF was cooled to -78° C., then 13.13 ml (21.0 mmol)of 1.6M solution of n-butyllithium in hexane was added dropwise and themixture was stirred for 15 minutes. To the reaction mixture was added asolution of 3.32 g (20.0 mmol) of bicyclo[2.2.1]hept-5-en-2-endo,3-endo-dicarboxylic anhydride I-1 in 20 ml of THF and the resultingmixture was stirred for an hour at -78° C. The reaction mixture wasacidified with 2N hydrochloric acid and the product was extracted withethyl acetate. The organic layer was washed with water and an aqueoussolution of sodium chloride and concentrated to give 9.33 g of themixture of the aimed product II-1-D(e1) and its by-product II'-1-D(e1).The aimed product II-1-D(e1) was purified by column chromatography onsilica gel (toluene-ethyl acetate).

IR(film) ν max: 3600-2400, 1748, 1710, 1498, 1456, 1342, 1257, 1208,1165, 1084, 1072, 912, 732, 696 cm⁻¹.

¹ HNMR(CDCl₃ TMS) δ ppm: 1.33(ABq, Apart, J=8.9 Hz; 1H), 1.48(ABq,Bpart, J=8.9 Hz, 1H), 3.16(br. s, 1H), 3.21(br. s, 1H), 3.30(dABq,Apart, J=3.2, 10.2 Hz, 1H), 3.47(dABq, Bpart, J=3.4 Hz, 10.2 Hz, 1H),5.13(s, 2H), 5.97(s, 1H), 6.11(dABq, Apart, J=2.9 Hz, 5.9 Hz, 1H),6.28(dABq, Bpart, J=2.8, 5.9 Hz, 1H), 7.13˜7.52(m, 10H).

EXAMPLE 2-7

According to the procedure in Example 1, the reaction was conducted asshown by following reaction formula to give the aimed compounds II-D(e),II-D(a), and II-L(e). The reaction conditions are shown in Table 1.##STR19## wherein R⁵, X, Y, and Z each has the same meaning as definedbefore.

                                      TABLE 1                                     __________________________________________________________________________     ##STR20##                                                                     Ex. No.                                                                          ##STR21##                                                                           g (mmol)                                                                          D or LR.sup.5 (mmol)gesterMandelic acid and                                               ml (mmol)n-BuLi                                                                   g (mmol)ZnCl.sub.2                                                                Crude: g (Yield: %)II-D(e), II-D(a) or                                       II-L(e)         Compound                     __________________________________________________________________________                                                    No.                               ##STR22##                                                                          1.83 (11.2)                                                                       D   CH.sub.2 Ph                                                                       2.97 (12.3)                                                                       7.30 (11.7)                                                                       0.796 (5.84)                                                                      II-D(e) 5.75   II-1-D(e1)                    3                                                                                 ##STR23##                                                                          14.68 (89.4)                                                                      D   CHPh.sub.2                                                                        28.47 (89.4)                                                                      55.9 (89.4)                                                                       --  II-D(e) 43     II-1-D(e2)                    4                                                                                 ##STR24##                                                                          1.64 (9.99)                                                                       D   Me  1.82 (11.0)                                                                       6.40 (10.2)                                                                       --  II-D(e) 2.86 (87) (II-1-D(e3):II'-1-D(e3)                                      = 78:22       II-1-D(e3)                    5                                                                                 ##STR25##                                                                          47.6 (286)                                                                        D   Me  47.6 (287)                                                                        179 (286)                                                                         --  II-D(e) 91 (96) (II-2-D(e1):II'-2-D(e1)                                       = 82:18)       II-2-D(e1)                    6                                                                                 ##STR26##                                                                          1.66 (10.0)                                                                       D   H   1.52 (10.0)                                                                       12.5 (20.0)                                                                       --  II-D(e) 2.57 (81) (II-2-D(a1):II'-2-D(a1)                                      = 50:50)      II-2-D(a1)                    7                                                                                 ##STR27##                                                                          14.39 (86.6)                                                                      L   CHPh.sub.2                                                                        30.35 (95.3)                                                                      64.0 (96.0)                                                                       --  II-L(e) 56.77  II-2-L(e1)                    __________________________________________________________________________

In Table 1, the mixture of the aimed compound II-2-D(e1) and itsby-product II'-2-D(e1), which was prepared in Example 5, waschromatographed on silica gel with toluene-ethyl acetate to isolate 75 gof the aimed compound II-2-D(e1) in 78.6% isolated yield.

Anal. Calcd. (%) for C₁₈ H₂₀ O₆ 0.2H₂ O: C, 64.35; H, 6.13; Found (%):C, 64.37; H, 6.49.

¹ HNMR(CDCl₃ -TMS) δ ppm: 1.37˜2.00(m, 6H), 2.62(br. s, 2H), 3.06(dABq,Apart, J=3.0, 12.0 Hz, 1H), 3.22(dABq, Bpart, J=3.0, 12.0 Hz, 1H),3.74(s, 3H), 6.01(s, 1H), 7.33˜7.55 (m, 5H). [α]_(D) =-70.2°±0.6°(CHCl₃, C=1.965%, 24° C.)

The other products were treated with the same procedure to isolate thecompounds II-1-D(e1), II-1-D(e2), II-1-D(e3), II-2-D(a1), andII-2-L(e1), respectively.

EXAMPLE 8 Preparation of(1R,2R,3S,4S)-bicyclo[2.2.1]heptan-2,3-dicarboxylic acid, 2-(D-mandelicacid) ester II-2-D(a1) ##STR28##

To a solution of 4.06 g (10.0 mmol) of crude product II-1-D(e1) in 30 mlof methanol was added 0.4 g of 10% palladiumcarbon and the mixture wasstirred in a hydrogen atmosphere under ordinary pressure at roomtemperature for 1.5 hours. The reaction mixture was filtered to removethe catalyst and the filtrate was concentrated. The residue waspartitioned between ethyl acetate and 5% aqueous solution of sodiumhydrogencarbonate and the aqueous layer was separated. The organic layerwas extracted with water. The aqueous layers were collected and washedwith ethyl acetate. After acidification with 2N hydrochloric acid themixture was extracted with ethyl acetate. The organic layer was washedwith an aqueous solution of sodium chloride and concentrated to give3.14 g of the crude product II-2-D(a1) in 99% yield from acid anhydride.Compound II-2-D(a1): Compound II'-2-D(a1)=86: 14 (Determined by HPLC).

The desired compound II-2-D(a1) was isolated by recrystallization fromethyl acetate. (2.05 g, yield 64%).

A mother liquour was concenrated and the residue was recrystallized fromdichloromethane to give by-product II'-2-D(a1).

Compound II-2-D(a1)

Mp. 164°-166° C.

Anal. Calcd. (%) for C₁₇ H₁₈ O₆ : C, 64.13; H, 5.71; Found (%): C,63.83; H, 5.73.

¹ HNMR(CDCl₃, TMS) δ ppm: 1.46(br. s, 4H), 1.57˜1.75(m, 1H),1.84˜2.08(m, 1H), 2.40˜2.62(m, 2H), 3.02(dABq, Apart, J=3.6, 11.6 Hz,1H), 3.29(dABq, Bpart, J=4.4, 11.6 Hz, 1H), 5.86(s, 1H), 7.33˜7.65(m,5H).

[α]_(D) =-117.1°±0.8° (MeOH, c=1.934, 25° C.).

Compound II'-2-D(a1)

Mp. 157°-158° C.

Anal. Calcd. (%) C₁₇ H₁₈ O₆ : C, 64.13; H, 5.71; Found (%): C, 64.02; H,5.57.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 1.30˜1.66(m, 4H), 1.69˜1.87(m, 1H),1.96˜2.13(m, 1H), 2.60(br. s, 2H), 3.04(dABq, Apart, J=2.8, 12.1 Hz,1H), 3.13(dABq, Bpart, J=3.8, 12.1 Hz, 1H), 5.84(s, 1H), 7.33˜7.58(m,5H).

[α]_(D) =-81.8°±0.6° (MeOH, C=2,005%, 25° C.)

EXAMPLE 9

The compound II-1-D(e1) prepared in Example 2 was allowed to react bythe same procedure as described in Example 8 to give the followingdicarboxylic acid II-2-D(a1). ##STR29##

EXAMPLE 10

The compounds II-1-D(e3) and II-2-D(e1) which were prepared in Example 4and 5, respectively, were allowed to react with LiI in DMSO to giveabove-mentioned dicarboxylic acid II-2-D(a1).

EXAMPLE 11

The compound II-2-L(e1) prepared in Example 7 was allowed to react bythe same procedure as described in Example 8 to give the followingdicarboxylic acid II-2-L(a1). ##STR30##

Mp. 162°-164° C.

[α]_(D) =+113.2°±1.5° (MeOH, C=1.0075%, 23.5° C.).

EXAMPLE 12 Preparation of (1S, 2R, 3S,4R)-bicyclo[2.2.1]hept-5-en-2,3-dicarboxylic acid, 2-(D-mandelic acid)ester II-1-D(a1) ##STR31##

To a cooled solution to 0° C. of 43 g of the crude product II-1-D(e2) in60 ml of dichloromethane were added 18 ml of anisole and 50 ml oftrifluoroacetic acid and the mixture was stirred for 1 hour. Thereaction mixture was concentrated and the residue was partitionedbetween ethyl acetate and 5% aquous solution of sodium hydrogencarbonate. The aqueous layer was separated, washed with ethyl acetate,acidified with 2N hydrochloric acid, and extracted with ethyl acetate.The organic layer was washed with a saturated aqueous solution of sodiumchloride, concentrated, and dried to give a crude II-1-D(a1)[II-1-D(a1):II'-1-D(a1)=74:26 (Determined by HPLC). The crude productwas recrystallized from ethyl acetate to give 13.37 g of aimed compoundII-1-D(a1) in 47% yield

Mp. 169°-171° C.

Anal. Calcd. (%) for C₁₇ H₁₆ O₆ : C, 64.55; H, 5.10; Found (%): C,64.46; H, 5.12.

IR(CHCl₃): 3500-2400, 1734, 1438, 1375, 1342, 1256, 1168, 1146, 1072cm⁻¹.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 1.36(ABq, Apart, J=7.2 Hz; 1H), 1.51 (ABq,Bpart, J=7.2 Hz, 1H), 3.15(br. s, 2H), 3.43(dABq, Apart, J=2.9, 10.4 Hz,1H), 3.53(dABq, Bpart, J=3.1, 10.4 Hz, 1H), 5.86(s, 2H), 6.14˜6.33(m,2H), 7.32˜7.62(m, 5H).

[α]_(D) =-159.5°±1.0° (MeOH, C=1.993%, 24° C.).

EXAMPLE 13

According to the procedure in Examples 1 and 8, the reaction using thecompound I-2 was conducted to give the aimed compound II-2-D(a1)##STR32##

Bicyclo[2.2.1]heptan-2-endo,3-endo-dicarboxylic anhydride I-2 (1.66 g,10.0 mmol) was allowed to react with 2.66 g (11.0 mmol) of benzylD-mandelate in the presence of 6.40 ml (10.2 mmol) of n-BuLi. Withoutpurification, the intermediate II-2-D(e2) was subjected tohydrogenolysis to give 2.64 g of the crude aimed product II-2-D(a1) inyield 83% (II-2-D(a1):II'-2-D(a1)=80:20), which was recrystallized fromethyl acetate to isolate 1.47 g of the aimed II-2-D(a1) in 46% yield.

The intermediate II-2-D(e2) can be purified by column chromatography onsilica gel.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 1.32˜1.97(m, 6H),2.55(br. s, 1H), 2.60(br. s,1H), 2.98(dABq,Apart, J=3.7, 11.6 Hz, 1H), 3.18(dABq, Bpart, J=3.9, 11.6Hz, 1H), 5.14(s, 2H), 6.03(s, 1H), 7.15˜7.52 (m, 10H)

EXAMPLES 14 to 16

The reaction was conducted according to the procedure in Example 13 togive the aimed product II-2-D(a1). The reaction conditions are shown inTable 2.

                                      TABLE 2                                     __________________________________________________________________________     ##STR33##                                                                     Ex. No.                                                                          ##STR34##                                                                           g (mmol)                                                                          R.sup.5 (mmol)gD-Mandelate                                                                     ml (mmol)n-Buli                                                                   MgBr.sub.2                                                                          II-D(e)                                                                             Crude Yield: g [Crude                                                        Yield (%)]II-D(a)Compd.         __________________________________________________________________________                                                  No.                             14                                                                                ##STR35##                                                                          1.64 (10.0)                                                                       CH.sub.2 Ph  2.67 (11.0)                                                                       6.60 (10.6)                                                                       Mg: 0.125 (g) 5.15 (mmol)                                                           II-1-D(e1)                                                                          2.24 (70) (II-2-D(a1):II'-2-                                                   D(a1) = 50:50                                                                          II-2-D(a1)            15                                                                                ##STR36##                                                                          1.42 (8.68)                                                                        ##STR37##   2.59 (9.51)                                                                       5.60 (8.96)                                                                       --    II-1-D(e4)                                                                          2.04 (74) (II-2-D(a1):II'-2-                                                   D(a1) = 82:18                                                                          II-2-D(a1)            16                                                                                ##STR38##                                                                           1.66 (10.0)                                                                      CHPh.sub.2   3.50 (11.0)                                                                       6.25 (10.0)                                                                       --    II-2-D(e3)                                                                          3.05* (96) (II-2-D(a1):II'-2                                                  - D(a1) = 73:27                                                                         II-2-D(a1)            __________________________________________________________________________     *Recrystallization from ethyl acetate gives 1.74 g of the aimed product i     55% isolated yield. The aimed product in Examples 14 and 15 also isolated     in the same method.                                                      

EXAMPLE 17 Preparation of(1R,2S,3S,4S)-2-methoxycarbonyl-3-carboxybicyclo[2.2.1]heptane III-2-D-1##STR39##

In a nitrogen atmosphere, a mixture of 5.51 g (17.3 mmol) of compoundII-2-D(a1),40 ml of THF, 50 ml of methanol, and 22.0 ml (44.0 mmol) ofsodium methoxide (2M solution in methanol) was refluxed for 4 hours. Tothe reaction mixture was added 2N hydrochloric acid and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand a saturated aqueous solution of sodium chloride, and concentrated.The residue was dissolved in dichloromethane and washed three times withwater. The organic layer was concentrated to give 3.22 g of the desiredcompound III-2-D-1 in 94% yield.

Mp. 59°-60° C.

Anal. Calcd. (%) for C₁₀ H₁₄ O₄ : C, 60.58; H, 7.13; Found (%): C,60.66; H, 7.08.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 1.20˜1.74(m, 6H), 2.59(br. s, 1H), 2.69(br.s, 1H), 2.79(d, J=5.4 Hz, 1H), 3.27(dd, J=3.8, 5.4 Hz, 1H), 3.69(s, 3H).

[α]_(D) =+38.4°±0.4° (MeOH, c=2.002, 25° C.).

EXAMPLE 18 Preparation of(1S,2R,3R,4R)-2-methoxycarbonyl-3-carboxybicyclo[2.2.1]heptane III-2-L-1##STR40##

According to the procedure in Example 17, the reaction using thecompound II-2-L(a1) as a starting material was conducted. CompoundII-2-L(a1) was an enantiomer of the starting material in Example 17. Thereaction was carried out under following conditions:

15.27 g (48.0 mmol) of the compound II-2-L(a1),

55 ml of methanol,

60 ml of THF, and

60 ml (120 mmol) of sodium methoxide (2M in methanol); to give 7.46 g ofthe aimed compound III-2-L-1 in 78% yield.

Mp. 59°-60° C.

[α]_(D) =-38.3°±0.4° (MeOH, C=2.013%, 25° C.).

EXAMPLE 19 Preparation of(1S,2S,3S,4R)-3-carboxy-2-methoxycarbonylbicyclo[2.2.1]hept-5-eneIII-1-D-1 ##STR41##

According to the procedure in Example 17, 15 g (47.4 ml) of the compoundII-1-D(a1) was allowed to react with 71.1 ml (142 mmol) of sodiummethoxide (2M in methanol) in 50 ml of methanol and 100 ml of THF togive 7.96 g of the aimed compound III-1-D-1 in 93.2% yield.

Mp. 78°-79° C.

Anal. Calcd. (%) for C₁₀ H₁₂ O₄ : C, 61.21; H, 6.17; Found (%): C,60.89; H, 6.13.

IR(CHCl₃): 3400-2400, 1729, 1708, 1438, 1422, 1335, 1311, 1271, 1245,1190, 1175, 1162, 1114, 1022 cm⁻¹.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 1.48(ABq, Apart, J=8.0 Hz, 1H), 1.63(ABq,Bpart, J=8.0 Hz, 1H), 2.66(dd, J=1.6, 4.6 Hz, 1H), 3.14(br. s, 1H),3.30(br. s, 1H), 3.43(dd, J=3.6, 4.6 Hz, 1H) 3.73(s, 3H), 6.14(dABq,Apart, J=2.9, 5.5 Hz, 1H), 6.29(dABq, Bpart, J=3.1, 5.5 Hz, 1H).

[α]_(D) =+138.1°±0.9° (MeOH, C=2.005%, 24° C.).

EXAMPLE 20 Preparation of(1R,2R,3S,4S)-bicyclo[2.2.1]heptan-2,3-dicarboxylic acid, 2-(D-mandelicacid) ester II-2-D(a1) ##STR42##

In a nitorgen atmosphere, 0.447 g (11.1 mmol) of 60% sodium hydride waswashed with hexane, dried under reduced pressure, and suspended in 10 mlof THF. To the suspension was added a solution of 2.69 g (11.1 mmol) ofbenzyl D-mandelate in 30 ml of THF and the mixture was stirred for 30minutes. The reaction mixture was cooled to -78° C. and a solution of1.64 g (10.0 mmol) of bicyclo[2.2.1]hept-5-en-2-endo,3-endo-dicarboxylic anhydride I-1 in 10 ml of THF was added dropwise.After addition, the resulting mixture was warmed to 0° C. understirring. The usual workup gives the half-ester, which was subjected todeprotection according to the procedure in Example 8 to give 2.04 g ofthe crude product in 64% yield. (Compound II-2-D(a1): CompoundII'-2-D(a1)=59:41).

EXAMPLE 21 Preparation of(1R,2R,3R,4S)-bicyclo[2.2.1]hept-5-en-2,3-dicarboxylic acid, 2-methylester III-1-L-1 ##STR43##

According to the procedure in Example 1, the reaction usingp-methoxybenzyl L-mandelate in place of benzyl D-mandelate was conductedto give a crud product mainly containing the compound II-1-L(e4), whichwas subjected to further reaction without isolation.

To a solution of 30.6 g (70 mmol) of the above crude product in 160 mlof acetonitrile was added 35.9 ml (70 mmol×6) of conc. hydrochloric acidand the mixture was stirred for 16 hours at room temperature. Thereaction mixture was adjusted to pH 4 with 4N NaOH, then made alkalinewith an aqueous sodium hydrogencarbonate under ice-cooling, and thenwashed with ethyl acetate. The organic layer was further extracted withwater and the combined aqueous layer was acidified with conc.hydrochloric acid to pH 2 and extracted with ethyl acetate. The organiclayer was washed with water, dried over anhydrous sodium sulfate,concentrated under reduced pressure to give a crystalline residue. Thecrude product (mixture of II-1-L(al) and II'-1-L(al) in the ratio of85:15 (by HPLC)) was recrystallized with ethyl acetate to give 11.2 g ofthe compound II-1-L(al) in 50.2% yield.

mp. 168° to 170° C.

The IR and ¹ H-NMR data of the compound II-1-L(al) were identical withthose of compound II-1-D(al), respectively. [α]_(D) =+160.5°±1.0° (MeOH,23.5° C., c=2.002%)

According to the procedure in Example 17, 345 mg of the compoundIII-1-L-1 was prepared from 601 mg of the compound II-1-L(al) in 92.7%yield. [α]_(D) =-140.8°±0.9° (MeOH, 23° C., c=2.018%)

mp. 78°-79° C.

EXAMPLE 22 Preparation of(1R,2S,3R,4S)-7-oxabicyclo[2.2.1]heptan-2,3-dicarboxylic acid,2-D-mandelic acid ester II-3-D(al) ##STR44##

According to the procedure in Examples 1 and 8, the mixture of thecompounds II-3-D(al) and II'-3-D(al) was prepared from 10.5 g (62 mmol)of the compound I-3. (II-3-D(al): II'-3-D(al)=73: 27 (by HPLC)). Fromthe mixture, 7.1 g of the compound II-3-D(al) and 1.5 g of the compoundII'-3-D(al) was isolated by recrystallization in 35.8% and 7.6% yield,respectively.

Compound II-3-D(al)

mp. 175°-177° C.

Anal. Calcd. (%) for C₁₆ H₁₆ O₇ : C, 59.99; H, 5.04; Found (%): C,59.85; H, 5.04.

¹ HNMR(CD₃ OD-TMS) δ ppm: 1.55˜1.88(m,4H), 3.13(ABq, A-part, J=9.6 Hz,1H), 3.19 (ABq, B-part, J=9.6 Hz, 1H), 4.83˜4.90(m, 2H), 5.85(s,1H),7.35˜7.65(m,5H).

IR(Nujol) ν max: 3480˜2200, 1733, 1712, 1659, 1229, 1220, 1185, 1011,969, 936, 766, 735, 696 cm⁻¹. [α]_(D) -111.9°±1.5° (MeOH, 23° C.,C=1.013%)

Compound II'-3-D(al)

mp. 133°-135° C.

Anal. Calcd. (%) for C₁₆ H₁₆ O₇. 0.5H₂ O: C, 58.35; H, 5.21; Found (%):C, 58.33; H, 5.48.

¹ HNMR(CD₃ OD-TMS) δ ppm: 1.55˜1.90(m,4H), 3.12(ABq, A-part, J=9.6 Hz,1H), 3.22(ABq, B-part, J=9.6 Hz, 1H), 4.75˜4.90(m, 2H), 5.74(s,1H),7.35˜7.65(m,5H).

IR(Nujol) ν max: 3680˜2200, 1733, 1710(sh), 1230, 1177 1044, 994, 925,819, 724 cm⁻¹. [α]_(D) -92.0°±1.3° (MeOH, 23° C., C=1.014%).

EXAMPLE 23 Preparation of(1R,2R,3R,4S)-7-oxabicylo[2.2.1]heptan-2,3-dicarboxylic acid, 2-methylester III-3-D-1 ##STR45##

According to the procedure in Example 17, 190 mg of the compoundIII-3-D-1 was prepared from 610 mg (1.9 mmol) of the compound II-3-D(al)in 50.0% yield.

mp. 134°-135° C.

Anal. Calcd. (%) for C₉ H₁₂ O₅ : C, 54.00; H, 6.05; Found (%): C, 53.98;H, 5.97.

¹ HNMR(CDCl₃ -TMS) δ ppm: 1.45˜1.95(m,4H), 3.14(d, J=5.1 Hz, 1H),3.50(t-d, J=5.5, 1.5 Hz, 1H), 3.74(s,3H), 4.84(t, J=5.0 Hz, 1H), 4.92(d,J=5.0 Hz, 1H).

IR(Nujol) ν max: 3400˜2480, 1736, 1725, 1255, 1215, 1201, 1184, 1173,921, 816 cm⁻¹. [α]_(D) +73.3°±0.6° (MeOH, 24° C., C=2.009%).

EXAMPLE 24 Preparation of(1S,2S,3S,4R)-7-oxabicylo[2.2.1]heptan-2,3-dicarboxylic acid, 2-methylester III-3-L-1 ##STR46##

According to the above mentiond procedure, the compound III-3-L-1,enantiomer of the compound III-3-D-1, was prepared from the by-productof the cleavage reaction, i.e. the compound II'-3-D(al) in 27.5% yield.

mp. 133°-134° C.

Anal. Calcd. (%) for C₉ H₁₂ O₅ : C, 54.00; H, 6.05; Found (%): C, 54.03;H, 6.06.

The ¹ HNMR and IR data were identical with those of the compoundIII-3-D-1, respectively. [α]_(D) -73.5°±0.6° (MeOH, 23° C., C=2.013%).

EXAMPLE 25 Preparation of(1S,2R,3S,4R)-7-oxabicyclo[2.2.1]heptan-2,3-dicarboxylic acid, 2-methylester III-3-D-2 ##STR47##

By a usual manner, 4.5 g (14.05 mmol) of the compound II-3-D(al) wastreated with a solution of diazomethane in ether to give 4.77 g of thecompound II-3-D(e5) in 97.5% yield.

Dimethyl ester II-3-D(e5)

mp. 131°-132° C.

Anal. Calcd. (%) for C₁₈ H₂₀ O₇ : C, 62.05; H, 5.80; Found (%): C,61.87; H, 5.78.

¹ HNMR(CDCl₃ -TMS) δ ppm: 1.45˜1.70(m,2H), 1.77˜1.93(m,2H), 2.99(ABq,A-part, J=9.6 Hz, 1H), 3.15(ABq, B-part, J=9.6 Hz,1H), 3.53(s, 3H),3.70(s,3H), 4.85˜4.93(m,1H), 4.95˜5.03 (m,1H), 5.93(s,1H),7.34˜7.55(m,5H).

IR(Nujol) ν max: 1742, 1732, 1198, 1143, 1055, 1009, 936, 725, 695 cm⁻¹.

[α]_(D) -103.2°±1.4° (CHCl₃, 23.5° C., C=1.009%).

To a solution of 4.18 g (12 mmol) of dimethyl ester II-3-D(e5) in 30 mlof ethyl acetate is added 400 mg of 10% Pd-C and the mixture was stirredfor 1 hour in a hydrogen atmosphere. The catalyst was removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidue was recrystallized from ether to give 2.02 of the cis-half esterIII-3-D-2 in 84.2% yield.

mp. 104°-106° C. Anal. Calcd. (%) for C₉ H₁₂ O₅ : C, 54.00; H, 6.05;Found (%): C, 53.83; H, 6.04.

¹ HNMR(CDCl₃ -TMS) δ ppm: 1.45˜1.60(m,2H), 1.73˜1.93(m,2H), 3.01(ABq,A-part, J=9.6 Hz, 1H), 3.03(ABq, B-part, J=9.6 Hz,1H), 3.66(s, 3H),4.87˜5.03(m,2H), 6.56(br,s 1H).

IR(Nujol)ν max: 3400˜2480, 1736, 1731, 1228, 1198, 1169, 1010, 996, 924,900, 821 cm⁻¹.

[α]_(D) -4.9°±0.2° (MeOH, 23.5° C., C=2.010%).

[α]₃₆₅ -7.9°±0.2° (MeOH,23.5° C., C=2.010%).

This product had the nearly same [α]_(D) value of the compound III-3-D-2reported by R. Bloch et al. (Tetrahedron Letters, 26, No. 34, pp.4087-4090 (1985) ([α]_(D) -3.9° (MeOH, 20° C., C=2%), mp. 104° C.)).

EXAMPLE 26 Preparation of(1R,2S,3R,4S)-7-oxabicyclo[2.2.1]heptan-2,3-dicarboxylic acid, 2-methylester III-3-L-2 ##STR48##

According to the procedure by which the compound II-3-D(e5) was preparedfrom the compound II-3-D(a1), the reaction was conducted using 720 mg(2.25 mmol) of the by-product II'-3-D(a1) of the cleavage reaction togive 678 mg of the compound II'-3-D(e5) in 86.6% yield.

Dimethyl ester II'-3-D(e5)

mp. 115°-116° C.

Anal. Calcd. (%) for C₁₈ H₂₀ O₇ : C, 62.05; H, 5.80; Found (%): C,61.85; H, 5.74.

¹ HNMR(CDCl₃ -TMS) δ ppm: 1.45˜1.70(m,2H), 1.74˜1.95(m,2H), 2.97(ABq,A-part, J=9.6 Hz, 1H), 3.17(ABq, B-part, J=9.6 Hz,1H), 3.36(s, 3H),3.71(s,3H), 4.84˜4.95(m,1H), 5.00˜5.10 (m,1H), 5.89(s,1H),7.33˜7.50(m,5H).

IR(Nujol) ν max: 1753, 1737, 1725, 1220, 1190, 1164, 1145, 1056, 1028,1004, 817, 735, 693 cm⁻¹.

[α]_(D) -84.7°±1.2° (CDCl₃, 23° C., C=1.008%).

According to the procedure by which the compound III-3-D-2 was preparedfrom the compound II-3-D(e5), the reaction was conducted using 523 mg(1.5 mmol) of dimethyl ester II'-3-D(e5) to give 271 mg of the cis-halfester III-3-L-2 in 90.3% yield.

mp. 103°-105° C.

Anal. Calcd. (%) for C₉ H₁₂ O₅.O.1H₂ O: C, 53.51; H, 6.10; Found (%) C,53.67; H, 5.90.

The ¹ HNMR and IR data were identical with those of the compoundIII-3-D-2, respectively.

[α]_(D) +4.4°±0.2° (MeOH, 24° C., C=2.006%).

[α]₃₆₅ +7.0°±0.2° (MeOH, 24° C., C=2.006%).

EXAMPLE 27 Preparation of(1R,2R,3S,4S)-2-(methyl-D-mandeloxycarbonyl)-3-methoxycarbonylbicyclo[2.2.1]heptaneII-2-D(e5) ##STR49##

A mixture of 22.72 g (71.3 mmol) of the compound II-2-D(a1) and 2.73 g(14.3 mmol) of p-toluenesulfonic acid mono-hydrate in 375 ml of methanolwas refluxed for 24 hours. The reaction mixture was concentrated and theresidue was partitioned between 5% aqueous sodium hydrogencarbonate andethyl acetate. The organic layer was washed with water, dried, andconcentrated to give 26.06 of the crude aimed product, which wasrecrystallized from ether/petroleum ether to give 18.59 g (53.7 mmol) asfirst crop, 0.62 g (1.8 mmol) as second crop, and 0.53 g (1.5 mmol) asthird crop (total isolated yield: 19.74 g (yield; 79.9%) of the aimedcompound II-2-D(e5).

mp. 61.5°-63.5° C.

Anal. Calcd. (%) for C₁₉ H₂₂ O₆ : C 65.88, H 6.40; Found (%): C 65.72, H6.42.

IR(KBr) ν max: 3700˜3160, 2970, 2885, 1758, 1745, 1730, 1457, 1365,1345, 1198, 1165, 1122, 1082, 1060, 1055, 1042, 1022, 748, 698 cm⁻¹.

¹ HNMR(CDCl₃ -TMS) δ ppm: 1.20˜2.00(m,6H), 2.50˜2.65(brm,2H), 2.96(dABq,A-part, J=3.8, 11.8 Hz), 3.21(dABq, B-part, J=4.3, 11.8 Hz), 3.54(s,3H),3.70(m,3H), 5.94(s,1H), 7.30˜7.52(m,5H).

[α]_(D) -77.8°±1.2° (CHCl₃, 23.5° C., C=1.00%).

EXAMPLE 28

Preparation of (1S,2S,3R,4R)-bicyclo[2.2.1]heptan-2,3-dicarboxylic acid,2-methyl ester III-2-D-2 ##STR50##

To 1.77 g of 10% palladium-carbon was added a solution of 17.79 g (51.4mmol) of the compound II-2-D(e5) in 200 ml of ethyl acetate and themixture was stirred for 50 minutes at room temperature under hydrogenatmosphere. The catalyst was removed by filtration and the filtrate wasconcentrated. Toluene and 5% aqueous sodium hydrogencarbonate were addedto the residue and the aqueous layer was separated. The organic layerwas extracted with water again. Each aqueous layer was washed withtoluene and the combined aqueous layer was acidified with 2Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with water, dried, and concentrated to give 10.2 g of theaimed compound III-2-D-2 quantitatively.

Anal. Calcd. (%) for C₁₀ H₁₄ O₄ : C 60.59, H 7.12; Found (%): C 60.42, H7.05.

IR(KBr) ν max: 3400˜2400, 2960, 2880, 1735, 1708, 1435, 1356, 1295,1288, 1132, 1122, 1082, 1058 cm⁻¹.

¹ HNMR(CDCl₃ -TMS) δ ppm: 1.35˜1.53(m,4H), 1.65˜1.88(m,2H),2.48˜2.64(brm,2H), 2.96(dABq, A-part, J=3.4, 11.7 Hz, 1H), 3.03(dABq,B-part, J=4.4, 11.7 Hz, 1H), 3.64(s,3H). [α]_(D) +17.1°±0.3° (MeOH,23.0° C., C=2.059%).

EXAMPLE 29

Preparation of(1S,2S,3R,4R)-2-(methyl-L-mandeloxycarbonyl)-3-methoxycarbonylbicyclo[2.2.1]heptaneII-2-L(e5) ##STR51##

According to the procedure in Example 27, the reaction was conductedusing the compound II-2-L(a1) to give the compound II-2-L(e5) in yield87.5%.

mp. 65.1°-62.5° C.

[α]_(D) +76.3°±1.2° (CHCl₃, 24° C., 1.005%).

EXAMPLE 30

Preparation of (1R,2R,3S,4S)-bicyclo[2.2.1]heptan-2,3-dicarboxylic acid,2-methyl ester III-2-L-2 ##STR52##

By the same manner as in Example 28, the reaction was subjected to givethe aimed compound III-2-L-2 quantitatively.

[α]_(D) -17.4°±0.3° (MeOH, C=2.052%, 24° C.).

Referential Example 1

Processes for Preparing Arylacetic Acid Derivatives

(1) Benzyl D-mandelate ##STR53##

A solution of 85.1 g (559 mmol) of D-mandelic acid, 65 ml (628 mmol) ofbenzyl alcohol, and 1.01 g (5.35 mmol) of p-toluenesulfonic acid in 700ml of benzene was refluxed for 6.5 hours. The mixture was washed withwater and concentrated. The residue was recrystallized from ether togive 123.5 g of the aimed compound D-2 in 91% yield.

Mp. 103.5°-105° C.

Anal. Calcd. (%) for C₁₅ H₁₄ O₃ : C, 74.36; H, 5.82; Found (%): C,74.53;H,5.90.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 3.44(d, J=5.6 Hz, 1H), 5.14(ABq, Apart,J=12.3 Hz, 1H), 5.22(d,J=5.6 Hz, 1H), 5.24(ABq, Bpart, J=12.3 Hz,1H)7.15˜7.50(m, 10H). [α]_(D) =-55.7±1.0 (CHCl₃, C=1.003%, 24° C.).

(2) 4-Methoxybenzyl D-madelate ##STR54##

A solution of 15.3 g (100 mmol) of D-mandelic acid, 15.2 g (110 mmol) of4-methoxybenzyl alcohol, and 0.197 g (1.01 mmol) of p-toluenesulfonicacid in 300 ml of benzene was refluxed for 7 hours. The mixture waswashed with water 4 times and concentrated. The residue was purified bycolumn chromatography on silica gel eluted with toluene-ethyl acetateand then by recrystallization from ether-petroleum ether to give 6.58 gof the aimed compound D-3 in 24% yield.

Mp. 70.5°-73.5° C.

Anal. Calcd. (%) for C₁₆ H₁₆ O₄ : C, 70.58; H, 5.92; Found (%): C,70.55; H, 6.00.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 3.80(s, 3H), 5.05(ABq, Apart, J=11.8 Hz, 1H),5.19(ABq, Bpart, J=11.8 Hz, 1H), 6.84(d, J=8.7 Hz, 2H), 7.17(d, J=8.7Hz, 2H), 7.30˜7.45(m, 5H). [α]_(D) =-36.0°±0.8° (CHCl₃, C=1.017%, 24°C.).

(3) 4-Nitrobenzyl D-mandelate ##STR55##

A solution of 15.2 g (100 mmol) of D-mandelic acid, 21.6 g (100 mmol) of4-nitrobenzyl bromide, and 14.0 ml (100 mmol) of triethylamine in 300 mlof DMF was stirred for 8 hours at room temperature. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed with 2N hydrochloric acid and water andrecrystallized from ether-petroleum ether to give 19.6 g of the aimedproduct D-4 in 68% yield.

Mp. 143°-145° C.

Anal. Calcd. (%) for C₁₅ H₁₃ NO₅ : C, 62.72; H, 4.56; N, 4.88; Found(%): C, 62.76; H, 4.61; N, 4.99.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 3.26˜3.52(br. s, 1H), 5.25(ABq, Apart, J=13.5Hz, 1H), 5.28(s, 1H), 5.32(ABq, Bpart, J=13.5 Hz, 1H), 7.27(d, J=8.4 Hz,2H), 7.34˜7.48(br. s, 5H), 8.14(d, J=8.4 Hz, 2H). [α]_(D) =-40.0°±0.8°(CHCl₃, C=0.995%, 24° C.).

(4) Benzhydryl D-mandelate ##STR56##

To a solution of 25.0 g (164 mmol) of D-mandelic acid in 200 ml of ethylacetate was added 38.9 g (164 mmol) of diphenyldiazomethane understirring at room temperature. The completeness of reaction was monitoredby TLC and the reaction mixture was concentrated. The residue wasrecrystallized from ether-petroleum ether to give 47.7 g of the aimedproduct D-5 in 91% yield.

Mp. 91°-91.5° C.

Anal. Calcd. (%) for C₂₁ H₁₈ O₃ : C, 79.22; H, 5.71; Found (%): C,79.44; H, 5.67.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 3.47(d, J=5.3 Hz, 1H), 5.28(d, J=5.3 Hz, 1H),6.87(s, 1H), 6.87˜7.46(m, 15H). [α]_(D) =-57.4°±1.0° (CHCl₃, C=1.023%,24° C.).

(5) Benzhydryl L-mandelate ##STR57##

According to the procedure in Referential Example 1-(4), the desiredcompound was obtained by reacting 30.4 g (200 mmol) of L-mandelic acidwith 38.9 g (200 mmol) of diphenyldiazomethane in 200 ml of ethylacetate to give 54.7 g (172 mmol) of the compound L-2 in 86% yield.

Mp. 91.5°-92.0° C.

[α]_(D) =+55.7°±0.9° (CHCl₃, C=1.013%, 24° C.).

Referential Example 2

A use of the compound (III) prepared in this invention was exemplifiedas follows. ##STR58##

In a nitrogen atmosphere, a solution of 2.80 g (14.1 mmol) of thecompound III-2-D-1 in 24 ml of acetone was cooled to 0° C. and 2.54 ml(18.3 mmol) of triethylamine and 1.75 ml (18.3 mmol) of ethylchlorocarbonate were added thereto. Then, colorless solids wereprecipitated immediately. The mixture was stirred for 15 minutes and asolution of 2.75 g (42.3 mmol) of sodium azide in 8 ml of water wasadded. The mixture was stirred under ice-cooling and acidified with 2Nhydrochloric acid. The resulting mixture was extracted with ethylacetate and the organic layer was washed with water and then with anaqueous solution of sodium chloride and concentrated. Benzene was addedto the residue and concentrated again in order to remove ethyl acetatecompletely.

The resulting oil was dissolved in 20 ml of benzene and the mixture washeated to 80° C. to perform thermal rearrangement. When the evolution ofnitrogen gas has ceased, 2.54 ml (18.3 mmol) of triethylamine and 1.75ml (16.9 mmol) of benzyl alcohol were added and the resulting mixturewas refluxed for 1.5 hours. After the reaction was finished, 2Nhydrochloric acid was added to the reaction mixture which was thenextracted with ethyl acetate. The organic layer was washed with water,and then with aqueous solution of sodium chloride and concentrated. Thecrude product was purified by column chromatography on silica gel andrecrystallized to give 3.03 g of the compound 1 in 71% yield.

Mp.: 61°-62° C.

Anal. Calcd. (%) for C₁₇ H₂₁ NO₄ : C, 67.30, H, 6.99; N, 4.62; Found(%): C, 67.46; H, 7.04; N, 4.73.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 1.22˜1.86(m, 6H), 1.92(dd, J=2.0, 5.0 Hz,1H), 2.50(br. s, 2H), 3.70(br. s, 3H), 4.23(br. s, 1H), 4.90(br. s, 1H),5.09(br. s, 2H), 7.22˜7.45(m, 5H).

[α]_(D) =+40.1°±0.4° (CHCl₃, c=2.006, 25° C.). ##STR59##

To a solution of 1.42 g (4.67 mmol) of the compound 1 in 13 ml ofmethanol was added 0.130 g of 10% palladium-carbon and the mixture wasstirred in a hydrogen atmosphere under ordinally pressure at roomtemperatuer for 30 minutes. The catalyst was removed by filtration andfiltrate was concentrated.

In a nitrogen atmosphere, a mixture of the prepared crude product in 10ml of dichloromethane was cooled to 0° C. and 1.94 ml (14.0 mmol) oftriethylamine and 0.66 ml (5.17 mmol) of benzenesulfonyl chloride wereadded thereto. The mixture was stirred for 30 minutes. The reactionmixture was acidified with 2N hydrochloric acid and then extracted withethyl acetate. The organic layer was washed with water and a saturatedaqueous solution of sodium chloride and concentrated. The residue waspurified by column chromatography on silica gel to give 1.17 g of theaimed compound 2 in 81% yield.

Mp. 129°-130° C.

Anal. Calcd. (%) for C₁₅ H₁₉ NO₄ S: C, 58.22; H, 6.20; N, 4.52; S,10.36; Found (%): C, 58.11; H, 6.07; N, 4.53; S, 10.09.

[α]_(D) =-0.4°±0.4° (CHCl₃, C=0.992%, 25° C.).

[α]₃₆₅ =-36.2°±0.8° (CHCl₃, C=0.992%, 25° C.). ##STR60##

In a nitrogen atmosphere, 0.412 g (10.9 mmol) of lithium aluminumhydride was added to a solution of 1.12 g (3.62 mmol) of compound 2 in15 ml of THF at room temperature and the mixture was stirred for 30minutes. In order to decompose the remaining lithium aluminum hydride,ethyl acetate and water were added to the reaction mixture,successively. The mixture was extracted with ethyl acetate (three times)and the organic layer was concentrated to give 1.00 g of the aimedcompound in 98.2% yield.

Mp. 121°-122° C.

Anal. Calcd. (%) for C₁₄ H₁₉ NO₃ S: C, 59.75; H, 6.82; N, 4.98; S,11.39: Found (%): C, 59.83; H, 6.91; N, 5.02; S, 11.33.

[α]_(D) =+6.8°±0.5° (CHCl₃, C=1.000%, 26° C.). ##STR61##

In a nitrogen atmosphere, 18.4 g (85.4 mmol) of PCC and 25.1 g ofmolecular sieves (4A powder) were added to a solution of 8.01 g (28.5mmol) of the compound 3 in 600 ml of dichloromethane and the mixture wasstirred at room temperature. The completeness of the reaction wasmonitored by TLC and the inorganic substances were removed by columnchromatography on silica gel. The eluate was concentrated to give theintermediate 4. Without further purification, the intermediate wassubjected to next reaction, since it was not so stable.

In a nitrogen atmosphere, 56.0 ml (84.0 mmol) of n-butyl lithium (1.6Min hexane) was added to a suspension of 31.20 g (91.0 mmol) ofmethoxymethyltriphenylphosphonium chloride in 160 ml of THF at -78° C.After addition, a dry ice bath was changed to an ice bath and themixture was stirred for 25 minutes at 0° C. The reaction mixture wascooled to -78° C. again in dry ice-acetone bath and a solution of 7.27 gof the above intermediate 4 in 80 ml of THF was added dropwise thereto.After addition, the ice bath was removed and the mixture was stirred for35 minutes. Ice-water was added to the reaction mixture, which wasextracted with ethyl acetate. The organic layer was washed with waterand a saturated aquoues solution of sodium chloride and thenconcentrated. The residue was chromatographed on silica gel to give theintermediate 5, which was subjected to next reaction without furtherpurification, as it was also unstable.

In a nitrogen atmosphere, 5.0 ml of 90% formic acid was added to 5.86 gof the compound 5 and the mixture was stirred for 1 hour at roomtemperature. The reaction was monitored by TLC and then the reactionmixture was neutralized with an aquoues solution of sodiumhydrogencarbonate. Water was added to the mixture, which was extractedwith ethyl acetate. The organic layer was washed with water and asaturated aqueous solution of sodium chloride and concentrated. Theresidue was purified by column chromatogrphy on silica gel to give 3.30g of the aimed compound 6 in 40% yield from the compound 3.

Compound 6

Mp. 100°-103° C.

Anal. Calcd. (%) for C₁₅ H₁₉ NO₃ S: C, 61.40; H, 6.54; N, 4.77; S,10.93; Found (%): C, 61.39; H, 6.51; N, 4.90; S, 11.02.

[α]_(D) =+36.5°±0.8° (CHCl₃, C=0.994%, 25.5° C.). ##STR62##

In a nitrogen atmosphere, 7.55 g (67.3 mmol) of potassium t-butoxide wasadded to a suspension of 14.8 g (33.3 mmol) of4-carboxylbutyltriphenylphosphonium bromide in 80 ml of THF at roomtemperature and the mixture was stirred for 1 hour at room temperatureand then cooled to -20° C.

A solution of 3.25 g (11.1 mmol) of the compound 6 in 20 ml of THF wasadded slowly to the above mixture and the mixture was stirred for about1.5 hour at -20° C. and stirred for additional one hour without an icebath. The reaction mixture was acidified with 2N hydrochloric acid andextracted with ethyl acetate. The extract was washed with water and asaturated aquoues solution of sodium chloride and then concentrated. Theprepared curde product was partitioned between toluene and 1N sodiumhydroxide and the aqueous layer was separated. The organic layer wasextracted with water again. The combined aqueous layer was acidifiedwith 2N hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with water and a saturated aquoue solution of sodiumchloride, dried over sodium sulfate, and concentrated. The residue waspurified by column chromatography on silica gel to give 3.29 g of theaimed compound 7 in 79% yield.

Mp. 62° C.

Anal. Calcd. (%): for C₂₀ H₂₇ NO₄ S: C, 63.63; H, 7.21; N, 3.71; S,8.49; Found (%): C, 63.56; H, 7.21; N, 3.83; S, 8.43.

[α]_(D) =+5.3°±0.5° (CHCl₃, C=1.003%, 22° C.).

[α]_(D) =+27.1°±0.7° (MeOH, C=1.015%, 24° C.).

Referential Example 3 ##STR63##

In a nitrogen atmosphere, a solution of 5.00 g (25.2 mmol) of thecompound III-2-L-2 in 25 ml of acetone was cooled to 0° C. and 3.90 ml(28.0 mmol) of triethylamine and 2.65 ml (27.7 mmol) of ethylchlorocarbonate were added thereto. Then, colorless solids wereprecipitated immediately. The mixture was stirred for 30 minutes and 6ml of aqueous solution of 1.72 g (26.5 mmol) of sodium azide was added.The mixture was stirred for 45 minutes under ice-cooling and acidifiedwith 2N hydrochloric acid. The resulting mixture was extracted withethyl acetate and the organic layer was washed with 5% aqueous solutionof sodium hydrogencarbonate, water, and an aqueous solution of sodiumchloride, dried, and concentrated. Benzene was added to the residue andconcentrated again in order to remove ethyl acetate completely.

The resulting oil was dissolved in 25 ml of benzene and the mixture washeated to perform thermal rearrangement. When the evolution of nitrogengas has ceased, 2.75 ml (26.5 mmol) of benzyl alcohol and 3.90 ml (28.0mmol) of triethylamine were added and the resulting mixture was refluxedfor 75 minutes. After the reaction was finished, 2N hydrochloric acidwas added to the reaction mixture which was then extracted with ethylacetate. The organic layer was washed with 5% aqueous solution of sodiumhydrogencarbonate, water, and an aqueous solution of sodium chloride andconcentrated. The crude product was purified by column chromatography onsilica gel with toluene-ethyl acetate to give 3.99 g (13.2 mmol) of theaimed compound 8 in 52.1% yield.

Anal. Calcd. (%) for C₁₇ H₂₁ NO₄ : C, 67.31; H, 6.98; N, 4.62; Found(%): C,67.12; H,6.96; N,4.63.

IR(CHCl₃) ν max: 3400, 2950, 2880, 1718, 1505, 1453, 1438, 1358, 1325,1316, 1163, 1152, 1080, 1062, 1035, 1028 cm⁻¹.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 1.32˜1.70(m, 6H), 2.49(br. s, 2H),2.93(dd,J=4.3 Hz, J=11.1 Hz, 1H), 3.63(s, 3H), 3.97˜4.18(m, 1H), 5.08(s,2H), 6.65˜6.83(br.m, 1H), 7.28˜7.44(m, 5H). [α]_(D) =+6.1°±0.5°(CHCl₃,C=1.010%,23.5° C.) [α]₃₆₅ =+28.5°±0.7° (CHCl₃,C=1.010%,23.5° C.)##STR64##

To a solution of 3.87 g (12.8 mmol) of the compound 8 in 15 ml ofmethanol was added 0.602 g of 10% palladium-carbon and the mixture wasstirred in a hydrogen atmosphere under ordinally pressure at roomtemperature for 100 minutes. The catalyst was removed by filtration andthe filtrate was concentrated.

In a nitrogen atmosphere, a mixture of the prepared crude product in 10ml of dichloromethane was cooled to 0° C. and 3.60 ml (25.8 mmol) oftriethylamine and 1.66 ml (13.0 mmol) of phenylsulfonyl chloride wereadded thereto. The mixture was stirred for 30 minutes. The reactionmixture was acidified with 2N hydrochloric acid and then extracted withethyl acetate. The organic layer was washed with 5% aqueous solution ofsodium hydrogencarbonate, water, and a saturated aqueous solution ofsodium chloride and concentrated. The residue was purified by columnchromatography on silica gel to give 3.20 g (10.3 mmol) of the aimedcompound 9 in 81.0% yield.

mp. 112.5°-113.5° C.

Anal. Calcd. (%) for C₁₅ H₁₉ NO₄ S: C, 58.23; H, 6.19; N, 4.53; S,10.36Found (%): C,58.33; H,6.19; N,4.45; S,10.08.

IR(KBr) ν max: 3335, 3270, 2965, 2880, 1705, 1445, 1435, 1368, 1352,1330, 1202, 1165, 1092, 905, 758, 732, 725, 690, 667, 586, 552 cm⁻¹.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 1.22˜1.76(m, 6H), 2.30(br. s, 1H), 2.43(br.s, 1H), 2.64(dd,J=4.8 Hz, J=10.6 Hz,1H), 3.51(s, 3H), 3.66˜3.82 (m, 1H),6.74(d,J=8.8 Hz, 1H), 7.42˜7.51(m, 3H), 7.77˜7.90(m, 2H).

[α]_(D) =-42.1°±0.8° (CHCl₃,C=1.002%,24° C.). ##STR65##

In a nitrogen atmosphere, to a suspension of 1.54 g of lithium aluminumhydride in 30 ml of THF was added a solution of 3.00 g (9.70 mmol) ofcompound 9 in 30 ml of THF and the mixture was stirred for 2 hour. Inorder to decompose the remaining lithium aluminum hydride, ethyl acetateand water were added to the reaction mixture, successively. The mixturewas extracted with ethyl acetate (three times) and the organic layer wasconcentrated to give 2.70 g of the aimed compound 10 in 99.0% yield.

mp. 97.5°-99.5° C.

Anal. Calcd. (%) for C₁₄ H₁₉ NO₃ S: C, 59.76; H, 6.81; N, 4.98; S,11.39;Found (%): C,59.68; H,6.77; N,4.92; S,11.14.

IR(KBr) ν max: 3640˜3360, 3260, 2960, 2890, 1482, 1463, 1448, 1340,1310, 1165, 1155, 1092, 1046, 955, 755, 718, 688, 595, 575, 549 cm⁻¹.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 1.16˜2.27(m, 10H), 3.40˜3.56(m, 1H),3.62(dABq, Apart, J=5.0, 11.0 Hz,1H), 3.81(dABq, Bpart, J=9.0, 11.0Hz,1H), 5.51˜5.78(br.m, 1H), 7.46˜7.70(m, 3H), 7.85˜8.00(m, 2H).

[α]_(D) =+35.1°±0.8° (CHCl₃, C=1.005%, 24.0° C.).

The racemate of the compound 10 can be separated into (+)-isomer and(-)-isomer by HPLC using chiral column. (ULTRON ES-OVM) ##STR66##

In a nitrogen atmosphere, to a suspension of 0.700 g (3.25 mmol) of PCCand 0.703 g of molecular sieves (4A powder) in 15 ml of dichloromethanewas added a solution of 0.304 g (1.08 mmol) of the compound 10 in 5 mlof dichloromethane under ice-cooling. The mixture was stirred for 45minutes at 0° C. and additional 45 minutes at 30° C. The completeness ofthe reaction was monitored by TLC and the inorganic substances wereremoved by passing through silica gel. The eluate was concentrated togive the mixture of the compounds 11a and 11b quantitatively. (11a:11b=9:1). Since the compound 11a was not so stable, it was graduallyconverted into the compound 11b during the isolation procedure.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 2.58˜2.66(br.m, 1H), 2.74˜2.88(m, 1H),3.64˜3.78(d,J=7.5 Hz, 1H), 9.49(s, 1H). (Only the characteristic signalsfor the compound 11a are shown.) ##STR67##

In a nitrogen atmosphere, 1.0 ml (0.200 mmol) of 0.2N sodium methoxidein methanol was added to a solution of 0.551 g (1.97 mmol) of themixture of the compounds 11a and 11b in 3.0 ml of methanol of and theresulting mixture was stirred for 60 minutes at room temperature. Thecompleteness of the reaction was monitored by TLC. The reaction mixturewas concentrated and the residue was partitioned between 2N hydrochloricacid and ethyl acetate. The organic layer was washed with water and asaturated aqueous solution of sodium chloride, dried, and concentratedto give 0.537 g of the aimed compound 11b in 97.5% yield.

mp. 100°-103° C.

Anal. Calcd. (%) for C₁₄ H₁₇ NO₃ S: C, 60.19; H, 6.13; N, 5.01; S,11.48;Found (%): C,60.08; H,6.09; N,5.11; S,11.41.

IR(KBr) ν max: 3250, 2960, 2940, 1712, 1462, 1448, 1338, 1325, 1158,1145, 1128, 1090, 1080, 753, 720, 682, 655, 590, 542 cm⁻¹.

¹ H-NMR(CDCl₃ -TMS) δ ppm: 1.05˜1.85(m, 6H), 2.18˜2.31(m, 2H), 2.45(d,J=3.6 Hz,1H), 3.81˜3.94(m,1H), 4.90˜5.05(br.m,1H), 7.40˜7.67(m,3H),7.76˜7.97(m, 2H), 9.55(s,1H).

[α]_(D) =-47.6°±0.9° (CHCl₃, C=1.009%, 24.0° C.).

The compound 11b thus prepared is identified with the compound 4prepared in Referential Example 2 (4). So it can be converted into thecompound 7 by the same procedure as in Referential Examples 2 (4) and(5).

We claim:
 1. An optically active mono-ester of a dicarboxylic acid ofthe formulas: ##STR68## wherein X is --O--; Y is --(CH₂)₂ --; R¹ isalkyl which may be substituted by alkoxy, halogen, amino, aminoderivative, or nitro or R¹ is alkenyl, aryl, or aralkyl, each of whichmay be substituted by alkyl, alkoxy, halogen, amino, amino derivative,or nitro or the enantiomer of said carboxylic acid esters of theaforementioned formulas.